Memory in Repetitive Protein-Protein Interaction Series -- in Memory of the Late Professor Robert M. Nerem

Over the past three decades, the senior author had interacted with and been mentored by the late Professor Robert M. Nerem. In his memory, the authors summarized several observations made, ideas conceptualized, and mathematical models developed during this period for quantitatively analyzing memory effects in repetitive protein-protein interactions (PPI). Interactions between proteins in an organism coordinate its biological processes and may impact its responses to changing environment and diseases through feedback systems. Feedback systems function by using changes in the past to influence behaviors in the future, which we refer here as memory. Specifically, we consider how proteins on cell or in isolation retain information about prior interactions to impact current interactions. The micropipette, biomembrane force probe and atomic force microscopic techniques were used to repeatedly assay several PPIs. The resulting time series were analyzed by a previous and two new models to extract three memory indices of short (seconds), intermediate (minutes), and long (hours) timescales. We found that interactions of cell membrane, but not soluble, T cell receptor (TCR) with peptide-major histocompatibility complex (pMHC) exhibits short-term memory that impacts on-rate, but not off-rate of the binding kinetics. Peptide dissociation from MHC resulted in intermediate- and long-term memories in TCR-pMHC interactions. However, we observed no changes in kinetic parameters by repetitive measurements on living cells over intermediate timescale using stable pMHCs. Parameters quantifying memory effects in PPIs could provide additional information regarding biological mechanisms. The methods developed herein also provide tools for future research.